Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden - PubMed (original) (raw)

doi: 10.1186/s40425-018-0344-8.

Carl Morrison 1 2 3 4, Jeffrey M Conroy 6 5, Mary K Nesline 5, Sean T Glenn 7 5, Devin Dressman 5, Antonios Papanicolau-Sengos 5, Blake Burgher 5, Jonathan Andreas 5, Vincent Giamo 5, Moachun Qin 5, Yirong Wang 5, Felicia L Lenzo 5, Angela Omilian 8, Wiam Bshara 8, Matthew Zibelman 9, Pooja Ghatalia 9, Konstantin Dragnev 10, Keisuke Shirai 10, Katherine G Madden 10, Laura J Tafe 10 11, Neel Shah 12, Deepa Kasuganti 12, Luis de la Cruz-Merino 13, Isabel Araujo 13, Yvonne Saenger 14, Margaret Bogardus 14, Miguel Villalona-Calero 15, Zuanel Diaz 15, Roger Day 16, Marcia Eisenberg 17, Steven M Anderson 17, Igor Puzanov 18, Lorenzo Galluzzi 19 20 21, Mark Gardner 5, Marc S Ernstoff 18

Affiliations

Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden

Carl Morrison et al. J Immunother Cancer. 2018.

Abstract

Background: Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma.

Methods: Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8+ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario.

Results: PD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity.

Conclusions: In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.

Keywords: Algorithmic analysis; Borderline; Immune Desert; Inflamed; Ipilimumab; Nivolumab; Pembrolizumab.

PubMed Disclaimer

Conflict of interest statement

Existing deidentified specimens and associated clinical data was submitted to OmniSeq from Roswell Park Comprehensive Cancer Center (Buffalo, NY), Fox Chase Cancer Center (Philadelphia, PA), Dartmouth-Hitchcock Medical Center (Lebanon, NH), Northwest Oncology (Munster, IN), Hospital Universitario Virgen Macarena (Sevilla, Spain), Columbia University (New York, NY), and Miami Cancer Institute (Miami, FL) with institutional review board approval from each individual institution. OmniSeq’s analysis utilized deidentified data that was considered non-human subjects research under IRB-approved protocol (BDR #073166) at Roswell Park Comprehensive Cancer Center (Buffalo, NY).

Competing interests

Disclosures: MZ, PG, KD, KS, KGM, LJT, NS, DK, LDLCM, IA, YS, MB, MVC, and ZD have no conflicts of interest to disclose. SP, JMC, MKN, STG, DD, APS, BB, JA, VG, MQ, YW, FLL, MG, and CM are all employees of OmniSeq, Inc. (Buffalo, NY) and hold restricted stock in OmniSeq, Inc. AO, WB, IP, CM, STG, JMC, and MSE are employees of Roswell Park Comprehensive Cancer Center (Buffalo, NY). Roswell Park Comprehensive Cancer Center is the majority shareholder of OmniSeq, Inc. MSE, RD, and LG provide remunerated consulting to OmniSeq, Inc. ME and SMA are employees of Laboratory Corporation of America Holdings (Burlington, NC). Laboratory Corporation of America Holdings, (Burlington, NC) is a shareholder in OmniSeq, Inc.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Fig. 1

Survival analysis of melanoma patients based on PD-L1 expression levels and mutational burden. a, b Overall survival upon stratification based on PD-L1 positivity (tumor proportion score ≥ 1% versus < 1%) for metastatic melanoma patients treated (a) prior to the introduction of ICIs (historical controls; n = 94) and (b) ICI-treated melanoma patients (n = 137). c, d Overall survival upon stratification based on mutational burden [high (≥ 7.1 mut/Mb) versus non-high] for metastatic melanoma patients treated (c) prior to the introduction of ICIs (historical controls; n = 94) and (d) ICI-treated melanoma patients (n = 137). _p_-values are indicated

Fig. 2

Fig. 2

Immunological landscape of melanoma and its association with multiple variables. a Unsupervised hierarchical clustering (rows = patients, columns = genes) for 394 immune transcripts identified three major groups defined as “inflamed” (group 1), “borderline” (group 2), and “immune desert” (group 3). CD8 (assessed by RNA-seq) and PD-L1 expression levels (assessed by immunohistochemistry), response to ICIs (as per RECIST v.1.1), CD8 infiltration pattern (assessed by a trained pathologist, CM and APS), and mutational burden (assessed by whole-exon sequencing) are depicted. b-d Overall survival for melanoma patients from the (b) inflamed (n = 131), (c) borderline (n = 81), and (d) immune desert (n = 88) groups upon stratification based on treatment (historical controls versus ICI-based immunotherapy). p values are reported

Fig. 3

Fig. 3

CD8+ T-cell infiltration pattern and clinical benefits from immune checkpoint inhibition. a CD8+ T-cell infiltration pattern was assessed by a trained pathologist upon immunohistochemistry with a CD8-specific antibody. Representative images are depicted (scale bar = 500 μm or 1 mm). b, c Overall survival upon stratification based on infiltration pattern (non-infiltrated, infiltrated, excluded) for metastatic melanoma patients treated (b) prior to the introduction of ICIs (historical controls; n = 94) and (c) ICI-treated melanoma patients (n = 137). For all comparisons p > 0.05

Fig. 4

Fig. 4

Predictive performance of the RS as compared to PD-L1 expression levels and mutational burden. a Response rates for mutational burden using a scale of very low, low, intermediate, high, and very high. While increasing response rates occur with an increase in mutational burden the range of values from 36% to 45% is also limited for clinical use. b Box plot shows a pair-wise comparison of mutational burden for CR, PR, SD, and PD. c Response rates for PD-L1 IHC using a tumor proportion score (TPS) with values of zero or negative, 1–4%, 5–10%, and > 10%. While increasing response rates occur with an increase in TPS the range of values from 40% to 100% is limited for clinical use. d Box plot shows a pair-wise comparison of PD-L1 IHC TPS for CR, PR, SD, and PD. e Objective response rates in groups of ICI-treated melanoma patients stratified by RS. Linear regression supports a dynamic range from 30% to 100%. f Box plot shows a pair-wise comparison of RS values for CR, PR, SD, and PD. g Overall survival upon stratification based on RS (≥ 50 versus < 50) for ICI-treated melanoma patients (n = 137), p value is indicated, for comprehensive immune profiling using response score (RS) with a bin width of 10. Response rate shows a dynamic range of values from near zero to greater than 95% with increasing RS. Survival curve for patients with a RS ≥ 50 and < 50 shows an improved survival for the former (p = 0.0012)

Similar articles

Cited by

References

    1. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with Ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–723. doi: 10.1056/NEJMoa1003466. - DOI - PMC - PubMed
    1. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus Dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–2526. doi: 10.1056/NEJMoa1104621. - DOI - PubMed
    1. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189–2199. doi: 10.1056/NEJMoa1406498. - DOI - PMC - PubMed
    1. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med. 2013;369:122–133. doi: 10.1056/NEJMoa1302369. - DOI - PMC - PubMed
    1. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372:2521–2532. doi: 10.1056/NEJMoa1503093. - DOI - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources